This invention is directed to novel vanilloid receptor VR1 ligands. More particularly, this invention relates to novel naphthol, quinoline and isoquinoline-derived ureas that are potent antagonists or agonists of VR1 and exhibit activity in animal models of hyperalgesia and colitis, and are useful for the treatment and prevention of pain conditions in humans including arthritis, and for the treatment of irritable-bowel syndrome and associated conditions.
Noxious chemical, thermal and mechanical stimuli excite peripheral nerve endings of small diameter sensory neurons (nociceptors) in sensory ganglia (e.g., dorsal root, nodose and trigeminal ganglia) and initiate signals that are perceived as pain. These neurons are crucial for the detection of harmful or potentially harmful stimuli (heat) and tissue damage (local tissue acidosis and/or stretch) that arise from changes in the extracellular space during inflammatory or ischaemic conditions (Wall, P. D., and Melzack, R., Textbook of Pain, 1994, New York: Churchill Livingstone). Nociceptors transduce noxious stimuli into membrane depolarization that triggers action potential, conducts the action potential from the sensory sites to the synapses in the CNS, and conversion of action potentials invokes a perception of pain, discomfort, and appropriate mechanical/physical protective reflexes. At the molecular level, nociception is carried out by ion channels or receptors. Plant derived vanilloid compounds (capsaicin and its ultrapotent analog, resiniferatoxin, etc.) are known to selectively depolarize nociceptors and elicit sensations of burning pain—the sensation that is typically obtained by hot chili peppers. Therefore, capsaicin mimics the action of physiological/endogenous stimuli that activates the “nociceptive pathway”. Recent advances in pain biology have identified receptors for vanilloids, protons (i.e., acidic solutions), and for heat. Because nociceptors are involved with unwanted pain and inflammatory conditions in human beings and animals, modulation of their nociceptive pathway is important in palliative and other therapies.
Walpole and colleagues at Sandoz reported on the first competitive antagonist of the sensory neuron excitants capsaicin and resineriferatoxin (Walpole, C. S. J. et. al., J. Med. Chem. 1994, 37, 1942). Subsequently, capsazepine has been shown to be a vanilloid receptor antagonist. Capsazepine, however, is not naphthol, quinoline and isoquinoline-derived. Jee Woo Lee and colleagues at Pacific Corporation disclosed thiocarbamic acid derived VR1 antagonists in WO0216317A1 and vanilloid receptor modulators in WO0216318A1 and WO0216319A1 but these applications do not disclose or describe N-naphthol, quinoline and isoquinoline-derived N′-benzylic ureas. Hutchinson and colleagues at Neurogen describe diaryl piperazinyl ureas and related compounds as capsaicin receptor ligands in WO02082212A1 but N-naphthol, quinoline and isoquinoline-derived N′-benzylic ureas are not covered. Scientists at the Universidad Miguel Hernandez in Alicante, the Universidad de Valencia and the Consejo Superior de Investigaciones Cientificas (CSIC) in Barcelona have used a combinatorial chemistry-based approach to discover compounds that modulate the vanilloid VR1 receptor and have disclosed two trialkylglycine-based compounds as noncompetitive VR1 channel blockers (Garcia-Martinez, C. et al. Proc Natl Acad Sci USA 2002, 99(4): 2374) but none are naphthol, quinoline and isoquinoline-derived.
Honma et al. disclose various urea compounds as Cdk4 inhibitors, including unsubstituted 5-naphth-3-ol-benzyl urea (J. Med. Chem. 2001, 44, 4615–4627). They do not, however, describe or suggest these or any other compounds as being modulators of VR and they do not describe or suggest the compounds of the present invention.
U.S. Pat. No. 6,001,860 discloses various bis-aryl and aryl arylalkyl ureas as inhibitors of acyl coenzyme A: cholesterol acyl transferase. This patent also does not describe or suggest these or any other compounds as being modulators of VR and does not describe or suggest the compounds of the present invention.
International patent publication number WO 00/71493A2 very broadly describes bis alkyl aryl and heteroaryl linked compounds, including urea moieties as linkers. These compounds are characterized as inhibitors of factor Xa. However, this publication does not describe or suggest these or any other compounds as being modulators of VR and does not describe or suggest the compounds of the present invention.
U.S. Pat. No. 5,610,192 very broadly describes bis aryl and heteroaryl linked compounds, including urea moieties as linkers. These compounds are characterized as inhibitors of metazoan parasite proteases. However, this patent also does not describe or suggest these or any other compounds as being modulators of VR and does not describe or suggest the compounds of the present invention.
Thus, there is a need for potent modulators of VR, and in particular, for novel naphthol, quinoline and isoquinoline-derived ureas that exhibit potent binding affinity for the human and rat VR1 ion channel. There is also a need for novel naphthol, quinoline and isoquinoline-derived ureas that act as potent functional antagonists and/or agonists of the human and rat VR1 ion channel. Finally, there is a need for novel naphthol, quinoline and isoquinoline-derived ureas that bind with high affinity to VR1 and also act as potent functional antagonists of the human and rat VR1 ion channel.